Wnt signal pathways are essential for development and have been implicated in tumorigenesis[1]. See also Reya & Clevers, Nature (2005), 434:843-850; Logan & Nusse, Annu. Rev. Cell Dev. Biol. (2004), 20:781-810; and US 2004/0247593. Disheveled (Dvl) proteins are scaffold proteins that play central role for both canonical and non-canonical Wnt signal pathways[2]. See also Wallingford & Habas, Development (2005), 132:4421-4436. Dvl proteins are composed of an N-terminal DIX domain, a central PDZ domain and a C-terminal DEP domain. Of these three, PDZ domain plays the most important role in Wnt signal transduction. Over 20 natural ligands have been reported bound to Dvl PDZ domain (hereinafter “DvlPDZ” or “Dvl PDZ”) [2-6], most of which have been indicated to be biologically important for canonical or non-canonical Wnt signal pathways. For example, the direct binding of DvlPDZ to an internal sequence in the C-terminal region of Frizzled has been reported to play an important role in Wnt signal pathway[3]. Over-expression of Dvl protein has been observed in several types of cancers, such as non-small cell lung cancer and mesothelioma [7,8], making Dvl a drug target for cancer treatment. Efforts have been made to develop specific antagonists to DvlPDZ based on the peptide ligand derived from Dapper and Frizzled[9]. However, the small molecule that was identified reportedly binds to DvlPDZ with very low affinity (Ki=237 μM), and the efficacy in vivo has not been fully addressed.
The important cellular functions ascribed to Dvl, in particular those mediated through the protein-protein interaction between DvlPDZ and its ligand(s), suggest that DvlPDZ represents a significant therapeutic target. It would therefore be beneficial to elucidate the mechanistic aspects of DvlPDZ-ligand interaction and provide compositions and methods targeted at modulating its associated functional activities. The present invention provides this and other benefits.